Common Genetic Variations Involved in the Inter-Individual Variability Of
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Heterozygous ATP-Binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease
bioRxiv preprint doi: https://doi.org/10.1101/780734; this version posted September 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease Short title: Heterozygous ABCG5 deficiency and risk of CAD Akihiro Nomura*, MD PhD, Connor A. Emdin*, DPhil, Hong Hee Won, PhD, Gina M. Peloso, PhD, Pradeep Natarajan, MD, Diego Ardissino, MD, John Danesh, FRCP DPhil, Heribert Schunkert, MD, Adolfo Correa, MD PhD, Matthew J. Bown, MD FRCS, Nilesh J. Samani, MD FRCP, Jeanette Erdmann, PhD, Ruth McPherson, MD, Hugh Watkins, MD PhD, Danish Saleheen, MD, Roberto Elosua, MD PhD, Masa-aki Kawashiri, MD PhD, Hayato Tada, MD PhD, Namrata Gupta, PhD, Svati H. Shah, MD MHS, Daniel J. Rader, MD, Stacey Gabriel, PhD, Amit V. Khera*, MD, Sekar Kathiresan*, MD *: These authors contributed equally Address for correspondence: Sekar Kathiresan, MD Verve Therapeutics 26 Landsdowne Street, 1st Floor Cambridge, MA 02139 Email: [email protected] Phone: 617 603 0070 bioRxiv preprint doi: https://doi.org/10.1101/780734; this version posted September 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Background: Familial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. -
Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia Akira Matsunaga1, Mariko Nagashima1, Hideko Yamagishi1 and Keijiro Saku2
The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article J Atheroscler Thromb, 2020; 27: 1264-1277. http://doi.org/10.5551/jat.51540 Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia Akira Matsunaga1, Mariko Nagashima1, Hideko Yamagishi1 and Keijiro Saku2 1Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan 2Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan Aim: Hypertriglyceridemia is a type of dyslipidemia that contributes to atherosclerosis and coronary heart dis- ease. Variants in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glyco- sylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation fac- tor 1 (LMF1), and glucokinase regulator (GCKR) are responsible for hypertriglyceridemia. We investigated the molecular basis of severe hypertriglyceridemia in adult patients referred to the Clinical Laboratory at Fukuoka University Hospital. Methods: Twenty-three adult patients with severe hypertriglyceridemia (>1,000 mg/dL, 11.29 mmol/L) were selected. The coding regions of candidate genes were sequenced by next-generation sequencing. Forty-nine genes reportedly associated with hypertriglyceridemia were analyzed. Results: In the 23 patients, we detected 70 variants: 28 rare and 42 common ones. Among the 28 rare variants with <1% allele frequency, p.I4533L in APOB, -
The Expression of the Human Apolipoprotein Genes and Their Regulation by Ppars
CORE Metadata, citation and similar papers at core.ac.uk Provided by UEF Electronic Publications The expression of the human apolipoprotein genes and their regulation by PPARs Juuso Uski M.Sc. Thesis Biochemistry Department of Biosciences University of Kuopio June 2008 Abstract The expression of the human apolipoprotein genes and their regulation by PPARs. UNIVERSITY OF KUOPIO, the Faculty of Natural and Environmental Sciences, Curriculum of Biochemistry USKI Juuso Oskari Thesis for Master of Science degree Supervisors Prof. Carsten Carlberg, Ph.D. Merja Heinäniemi, Ph.D. June 2008 Keywords: nuclear receptors; peroxisome proliferator-activated receptor; PPAR response element; apolipoprotein; lipid metabolism; high density lipoprotein; low density lipoprotein. Lipids are any fat-soluble, naturally-occurring molecules and one of their main biological functions is energy storage. Lipoproteins carry hydrophobic lipids in the water and salt-based blood environment for processing and energy supply in liver and other organs. In this study, the genomic area around the apolipoprotein genes was scanned in silico for PPAR response elements (PPREs) using the in vitro data-based computer program. Several new putative REs were found in surroundings of multiple lipoprotein genes. The responsiveness of those apolipoprotein genes to the PPAR ligands GW501516, rosiglitazone and GW7647 in the HepG2, HEK293 and THP-1 cell lines were tested with real-time PCR. The APOA1, APOA2, APOB, APOD, APOE, APOF, APOL1, APOL3, APOL5 and APOL6 genes were found to be regulated by PPARs in direct or secondary manners. Those results provide new insights in the understanding of lipid metabolism and so many lifestyle diseases like atherosclerosis, type 2 diabetes, heart disease and stroke. -
LRP2 Is Associated with Plasma Lipid Levels 311 Original Article
310 Journal of Atherosclerosis and Thrombosis Vol.14, No.6 LRP2 is Associated with Plasma Lipid Levels 311 Original Article Genetic Association of Low-Density Lipoprotein Receptor-Related Protein 2 (LRP2) with Plasma Lipid Levels Akiko Mii1, 2, Toshiaki Nakajima2, Yuko Fujita1, Yasuhiko Iino1, Kouhei Kamimura3, Hideaki Bujo4, Yasushi Saito5, Mitsuru Emi2, and Yasuo Katayama1 1Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan. 2Department of Molecular Biology-Institute of Gerontology, Nippon Medical School, Kawasaki, Japan. 3Awa Medical Association Hospital, Chiba, Japan. 4Department of Genome Research and Clinical Application, Graduate School of Medicine, Chiba University, Chiba, Japan. 5Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba, Japan. Aim: Not all genetic factors predisposing phenotypic features of dyslipidemia have been identified. We studied the association between the low density lipoprotein-related protein 2 gene (LRP2) and levels of plasma total cholesterol (T-Cho) and LDL-cholesterol (LDL-C) among 352 adults in Japan. Methods: Subjects were obtained from among participants in a cohort study that was carried out with health-check screening in an area of east-central Japan. We selected 352 individuals whose LDL-C levels were higher than 140 mg/dL from the initially screened 22,228 people. We assessed the relation between plasma cholesterol levels and single-nucleotide polymorphisms (SNPs) in the LRP2 gene. Results: -
The Effect of Statin Treatment on Intratumoral Cholesterol Levels and LDL Receptor Expression: a Window-Of-Opportunity Breast Ca
Feldt et al. Cancer & Metabolism (2020) 8:25 https://doi.org/10.1186/s40170-020-00231-8 RESEARCH Open Access The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression: a window-of- opportunity breast cancer trial Maria Feldt1,2* , Julien Menard1, Ann H. Rosendahl1,2, Barbara Lettiero1, Pär-Ola Bendahl1, Mattias Belting1,2,3 and Signe Borgquist1,4 Abstract Background: Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism. Methods: This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post- atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level. Results: In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. -
Participation of ABCA1 Transporter in Pathogenesis of Chronic Obstructive Pulmonary Disease
International Journal of Molecular Sciences Review Participation of ABCA1 Transporter in Pathogenesis of Chronic Obstructive Pulmonary Disease Stanislav Kotlyarov Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia; [email protected] Abstract: Chronic obstructive pulmonary disease (COPD) is the important medical and social problem. According to modern concepts, COPD is a chronic inflammatory disease, macrophages play a key role in its pathogenesis. Macrophages are heterogeneous in their functions, which is largely determined by their immunometabolic profile, as well as the features of lipid homeostasis, in which the ATP binding cassette transporter A1 (ABCA1) plays an essential role. The objective of this work is the analysis of the ABCA1 protein participation and the function of reverse cholesterol transport in the pathogenesis of COPD. The expression of the ABCA1 gene in lung tissues takes the second place after the liver, which indicates the important role of the carrier in lung function. The participation of the transporter in the development of COPD consists in provision of lipid metabolism, regulation of inflammation, phagocytosis, and apoptosis. Violation of the processes in which ABCA1 is involved may be a part of the pathophysiological mechanisms, leading to the formation of a heterogeneous clinical course of the disease. Keywords: chronic obstructive pulmonary disease; COPD; inflammation; ABCA1; reverse cholesterol transport; innate immune system Citation: Kotlyarov, S. Participation of ABCA1 Transporter in Pathogenesis of Chronic Obstructive 1. Introduction Pulmonary Disease. Int. J. Mol. Sci. Chronic obstructive pulmonary disease (COPD) is one of the most widespread dis- 2021, 22, 3334. https://doi.org/ eases, it has great medical significance due to the high frequency of temporary and per- 10.3390/ijms22073334 sistent disability and mortality. -
Proteomic Analysis of HDL from Inbred Mouse Strains Implicates APOE Associated with HDL in Reduced Cholesterol Effl Ux Capacity Via the ABCA1 Pathway
Supplemental Material can be found at: http://www.jlr.org/content/suppl/2015/12/15/jlr.M063701.DC1 .html ˔ Author’s Choice Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol effl ux capacity via the ABCA1 pathway Nathalie Pamir , 1, * Patrick Hutchins , * Graziella Ronsein , * Tomas Vaisar , * Catherine A. Reardon , † Godfrey S. Getz , † Aldons J. Lusis , § and Jay W. Heinecke * Downloaded from Department of Medicine,* University of Washington , Seattle, WA ; Department of Pathology, † University of Chicago , Chicago, IL ; and Department of Genetics, § University of California at Los Angeles , Los Angeles, CA Abstract Cholesterol effl ux capacity associates strongly Supplementary key words atherosclerosis • cardiovascular risk • mass and negatively with the incidence and prevalence of human spectrometry • high density lipoprotein • apolipoprotein E • ATP bind- CVD. We investigated the relationships of HDL’s size and ing cassette transporter A1 www.jlr.org protein cargo with its cholesterol effl ux capacity using APOB-depleted serum and HDLs isolated from fi ve inbred mouse strains with different susceptibilities to atherosclero- Clinical and epidemiological studies show a robust at Univ of Washington Health Sciences Library SB-55, on February 5, 2016 sis. Like humans, mouse HDL carried >70 proteins linked to inverse association of HDL-cholesterol (HDL-C) levels lipid metabolism, the acute-phase response, proteinase inhi- with CVD risk ( 1 ). In randomized clinical trials, how- bition, and the immune system. HDL’s content of specifi c ever, two drugs, CETP inhibitors and niacin, that elevate proteins strongly correlated with its size and cholesterol ef- fl ux capacity, suggesting that its protein cargo regulates its HDL-C levels by different mechanisms, failed to reduce function. -
Plasma Phospholipid Transfer Protein (PLTP) Modulates Adaptive Immune Functions Through Alternation of T Helper Cell Polarization
Cellular & Molecular Immunology (2016) 13, 795–804 OPEN ß 2016 CSI and USTC. All rights reserved 1672-7681/16 $32.00 www.nature.com/cmi RESEARCH ARTICLE Plasma phospholipid transfer protein (PLTP) modulates adaptive immune functions through alternation of T helper cell polarization Catherine Desrumaux1,2,3, Ste´phanie Lemaire-Ewing1,2,3,4, Nicolas Ogier1,2,3, Akadiri Yessoufou1,2,3, Arlette Hammann1,3,4, Anabelle Sequeira-Le Grand2,5, Vale´rie Deckert1,2,3, Jean-Paul Pais de Barros1,2,3, Naı¨g Le Guern1,2,3, Julien Guy4, Naim A Khan1,2,3 and Laurent Lagrost1,2,3,4 Objective: Plasma phospholipid transfer protein (PLTP) is a key determinant of lipoprotein metabolism, and both animal and human studies converge to indicate that PLTP promotes atherogenesis and its thromboembolic complications. Moreover, it has recently been reported that PLTP modulates inflammation and immune responses. Although earlier studies from our group demonstrated that PLTP can modify macrophage activation, the implication of PLTP in the modulation of T-cell-mediated immune responses has never been investigated and was therefore addressed in the present study. Approach and results: In the present study, we demonstrated that PLTP deficiency in mice has a profound effect on CD41 Th0 cell polarization, with a shift towards the anti-inflammatory Th2 phenotype under both normal and pathological conditions. In a model of contact hypersensitivity, a significantly impaired response to skin sensitization with the hapten-2,4-dinitrofluorobenzene (DNFB) was observed in PLTP-deficient mice compared to wild-type (WT) mice. Interestingly, PLTP deficiency in mice exerted no effect on the counts of total white blood cells, lymphocytes, granulocytes, or monocytes in the peripheral blood. -
Apoa5genetic Variants Are Markers for Classic Hyperlipoproteinemia
CLINICAL RESEARCH CLINICAL RESEARCH www.nature.com/clinicalpractice/cardio APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia 1 1 1 2 2 1 1 Jian Wang , Matthew R Ban , Brooke A Kennedy , Sonia Anand , Salim Yusuf , Murray W Huff , Rebecca L Pollex and Robert A Hegele1* SUMMARY INTRODUCTION Hypertriglyceridemia is a common biochemical Background Several known candidate gene variants are useful markers for diagnosing hyperlipoproteinemia. In an attempt to identify phenotype that is observed in up to 5% of adults. other useful variants, we evaluated the association of two common A plasma triglyceride concentration above APOA5 single-nucleotide polymorphisms across the range of classic 1.7 mmol/l is a defining component of the meta 1 hyperlipoproteinemia phenotypes. bolic syndrome and is associated with several comorbidities, including increased risk of cardio Methods We assessed plasma lipoprotein profiles and APOA5 S19W and vascular disease2 and pancreatitis.3,4 Factors, –1131T>C genotypes in 678 adults from a single tertiary referral lipid such as an imbalance between caloric intake and clinic and in 373 normolipidemic controls matched for age and sex, all of expenditure, excessive alcohol intake, diabetes, European ancestry. and use of certain medications, are associated Results We observed significant stepwise relationships between APOA5 with hypertriglyceridemia; however, genetic minor allele carrier frequencies and plasma triglyceride quartiles. The factors are also important.5,6 odds ratios for hyperlipoproteinemia types 2B, 3, 4 and 5 in APOA5 S19W Complex traits, such as plasma triglyceride carriers were 3.11 (95% CI 1.63−5.95), 4.76 (2.25−10.1), 2.89 (1.17−7.18) levels, usually do not follow Mendelian patterns of and 6.16 (3.66−10.3), respectively. -
The Crucial Roles of Apolipoproteins E and C-III in Apob Lipoprotein Metabolism in Normolipidemia and Hypertriglyceridemia
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Harvard University - DASH The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Sacks, Frank M. 2015. “The Crucial Roles of Apolipoproteins E and C-III in apoB Lipoprotein Metabolism in Normolipidemia and Hypertriglyceridemia.” Current Opinion in Lipidology 26 (1) (February): 56–63. doi:10.1097/mol.0000000000000146. Published Version doi:10.1097/MOL.0000000000000146 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:30203554 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#OAP HHS Public Access Author manuscript Author Manuscript Author ManuscriptCurr Opin Author Manuscript Lipidol. Author Author Manuscript manuscript; available in PMC 2016 February 01. Published in final edited form as: Curr Opin Lipidol. 2015 February ; 26(1): 56–63. doi:10.1097/MOL.0000000000000146. The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia Frank M. Sacks Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA Abstract Purpose of review—To describe the roles of apolipoprotein C-III (apoC-III) and apoE in VLDL and LDL metabolism Recent findings—ApoC-III can block clearance from the circulation of apolipoprotein B (apoB) lipoproteins, whereas apoE mediates their clearance. -
Lrp1 Modulators
Last updated on February 14, 2021 Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in- development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain health, as well as for age-related health concerns that can affect brain health (e.g., cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports include evaluation of safety data, from clinical trials if available, and from preclinical models. Lrp1 Modulators Evidence Summary Lrp1 has a variety of essential functions, mediated by a diverse array of ligands. Therapeutics will need to target specific interactions. Neuroprotective Benefit: Lrp1-mediated interactions promote Aβ clearance, Aβ generation, tau propagation, brain glucose utilization, and brain lipid homeostasis. The therapeutic effect will depend on the interaction targeted. Aging and related health concerns: Lrp1 plays mixed roles in cardiovascular diseases and cancer, dependent on context. Lrp1 is dysregulated in metabolic disease, which may contribute to insulin resistance. Safety: Broad-spectrum Lrp1 modulators are untenable therapeutics due to the high potential for extensive side effects. Therapies that target a specific Lrp1-ligand interaction are expected to have a better therapeutic profile. 1 Last updated on February 14, 2021 Availability: Research use Dose: N/A Chemical formula: N/A S16 is in clinical trials MW: N/A Half life: N/A BBB: Angiopep is a peptide that facilitates BBB penetrance by interacting with Lrp1 Clinical trials: S16, an Lrp1 Observational studies: sLrp1 levels are agonist was tested in healthy altered in Alzheimer’s disease, volunteers (n=10) in a Phase 1 cardiovascular disease, and metabolic study. -
ABCA1 Gene ATP Binding Cassette Subfamily a Member 1
ABCA1 gene ATP binding cassette subfamily A member 1 Normal Function The ABCA1 gene belongs to a group of genes called the ATP-binding cassette family, which provides instructions for making proteins that transport molecules across cell membranes. The ABCA1 protein is produced in many tissues, with high amounts found in the liver and in immune system cells called macrophages. This protein moves cholesterol and certain fats called phospholipids across the cell membrane to the outside of the cell. These substances are then picked up by a protein called apolipoprotein A-I (apoA-I), which is produced from the APOA1 gene. ApoA-I, cholesterol, and phospholipids combine to make high-density lipoprotein (HDL), often referred to as "good cholesterol" because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease. HDL is a molecule that carries cholesterol and phospholipids through the bloodstream from the body's tissues to the liver. Once in the liver, cholesterol and phospholipids are redistributed to other tissues or removed from the body. The process of removing excess cholesterol from cells is extremely important for balancing cholesterol levels and maintaining cardiovascular health. Health Conditions Related to Genetic Changes Familial HDL deficiency Mutations in the ABCA1 gene can cause a condition called familial HDL deficiency. People with this condition have reduced levels of HDL in their blood and may experience early-onset cardiovascular disease, often before age 50. While one copy of the altered ABCA1 gene causes familial HDL deficiency, two copies of the altered gene cause a more severe related disorder called Tangier disease (described below).